Substituted phenylacetonitriles

ABSTRACT

This application discloses certain substituted phenylacetonitriles of the formula: ##STR1## in which the dotted line represents optional unsaturation, and R 4  is hydrogen or alkyl; 
     R 5  and R 6 , one of which may be hydrogen, are ortho or para substituents, independently selected from the group consisting of hydroxyl, alkyl, alkoxy, aralkoxy, alkanoyloxy, alkylmercapto, halo or trifluoromethyl; 
     R 7  is hydrogen or alkyl; and 
     n is one of the integers 0, 1, 2, 3 or 4; 
     which are useful in the production of antidepressant agents.

This application is a division of U.S. patent application Ser. No.545,701, filed Oct. 26, 1983, U.S. Pat. No. 4,535,186 which applicationis a continuation-in-part of U.S. patent application Ser. No. 486,594,filed Apr. 19, 1983, now abandoned, which application is acontinuation-in-part of U.S. patent application Ser. No. 449,032, filedDec. 13, 1982, now abandoned.

DESCRIPTION OF THE INVENTION

In accordance with this invention there is provided a group ofsubstituted phenethylamine derivatives which are central nervous systemantidepressants. The compounds of this invention present the followingstructural formula: ##STR2## in which A is a moiety of the formula##STR3## where the dotted line represents optional unsaturation, or theanalogous cycloalkenyl moiety ##STR4##

R₁ is hydrogen or alkyl of 1 to 6 carbon atoms;

R₂ is alkyl of 1 to 6 carbon atoms;

R₄ is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2to 7 carbon atoms;

R₅ and R₆ are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbonatoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino,alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkylgroup is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms,halo, trifluoromethyl, or, when taken together, methylene dioxy;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and

n is one of the integers 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.

The preferred compounds are those of the formula: ##STR5## in which

A is defined supra;

R₁ is hydrogen or alkyl of 1 to 3 carbon atoms;

R₂ is alkyl of 1 to 3 carbon atoms;

R₅ is hydrogen, hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo,trifluoromethyl or alkyl of 1 to 3 carbon atoms;

R₆ is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,chloro, bromo, trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms.

R₇ is hydrogen or alkyl of 1 to 3 carbon atoms;

or a pharmaceutically acceptable salt thereof.

The most preferred compounds are those in which R₅ and R₆ are in meta orpara positions and n is 2.

The compounds in which R₄ is formyl or alkanoyl of 2 to 7 carbon atomsare not nearly as potent as the corresponding free hydroxy bearingderivatives in the test procedures employed and disclosed herein.However, in long term therapy the acyloxy derivatives will act as prodrugs as the acyl group is removed in vivo either via acid hydrolysis inthe stomach or enzymatically.

The pharmaceutically acceptable acid addition salts of the basiccompounds of this invention are formed conventionally by reaction of thefree base with an equivalent amount of any acid which forms a non-toxicsalt. Illustrative acids are either inorganic or organic, includinghydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric,phosphoric, tartaric, acetic, citric, oxalic and similar acids. Forparenteral administration, the use of water soluble salts is preferred,although either the free base of the pharmaceutically acceptable saltsare applicable for oral or parenteral administration of theantidepressant agents of this invention. The halo substituentrepresenting R₅ or R₆ is intended to include the chloro, bromo, iodo orfluoro substituents.

The compounds of this invention are produced by reaction of acycloalkanone or a cycloalkenone with an appropriately substituted(ortho or para) phenylacetonitrile anion following the procedure ofSauvetre et al., Tetrahedron, 34, 2135 (1978) followed by reduction(catalytic hydrogenation, borane reducing agents, LiAlH₄, etc.) of thenitrile to a primary amine and alkylation of the amine. In the presenceof cyclo aliphatic unsaturation, lithium aluminum hydride is thepreferred reducing agent. Subsequent acylation of the α-cycloaliphatichydroxyl group and any phenolic hydroxyl group present may be effectedconventionally with a formylating agent such as formyl fluoride or analkanoic acid halide or anhydride. Symmetrical N-methylation may beaccomplished via a modified Eschweiler-Clarke procedure employing alarge excess of water as illustrated by Tilford et al., J.A.C.S. 76,2431 (1954); alternatively the procedure of Borch and Hassid, J. Org.Chem., 37, 1653 (1972) using sodium cyanoborohydride and formaldehydemay be employed. Non-symmetrical N-alkylation or monoalkylation may beaccomplished by stepwise alkylation of the N-trifluoroacetate asillustrated by R. A. W. Johnstone et al., J. Chem. Soc., (C) 2223(1969). Where R₄ is alkyl it is introduced prior to reduction of thenitrile by conventional O-alkylation.

The intermediate nitriles prepared during the production of theantidepressant agents of this invention represent an additional aspectof the invention. They are depicted by the structural formula: ##STR6##in which the dotted line represents optional unsaturation, and R₄ ishydrogen or alkyl of 1 to 6 carbon atoms;

R₅ and R₆, one of which may be hydrogen, are ortho or para substituents,independently selected from the group consisting of hydroxyl, alkyl of 1to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aralkoxy of 7 to 9carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, alkylmercapto of 1 to6 carbon atoms, halo or trifluoromethyl;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and

n is one of the integers 0, 1, 2, 3 or 4.

The intermediate primary amines produced by reduction of the nitriledepicted in the preceding paragraph represent an additional aspect ofthe invention. They present the following structural formula: ##STR7##in which the dotted line represents optional unsaturation, R₄ ishydrogen, or alkyl of 1 to 6 carbon atoms;

R₅ and R₆ are ortho or para substituents independently selected from thegroup consisting of hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms,alkoxy of 1 to 6 carbon atoms, aralkoxy of 7 to 9 carbon atoms,alkanoyloxy of 2 to 7 carbon atoms, alkylmercapto of 1 to 6 carbonatoms, halo or trifluoromethyl;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and

n is one of the integers 0, 1, 2, 3 or 4.

Symmetrical N,N-dimethylation may be performed readily by reaction ofthe primary amino derivative with formaldehyde, formic acid in a largeexcess of water. An intermediate, 3-aza-1-oxaspiro[5.5]undecane, whichrepresents an additional intermediate of this invention is formed duringthe reaction and is isolatable. It presents the following structuralformula: ##STR8## in which the dotted line represents optionalunsaturation,

R₁ is methyl;

R₅ and R₆ are ortho or para substituents independently selected from thegroup consisting of hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms,alkoxy of 1 to 6 carbon atoms, aralkoxy of 7 to 9 carbon atoms,alkanoyloxy of 2 to 7 carbon atoms, alkylmercapto of 1 to 6 carbonatoms, halo or trifluoromethyl;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and

n is one of the integers 0, 1, 2, 3 or 4.

These oxaspiro[5.5]undecane intermediates possess similar activity tothe corresponding open-ring tertiary amino end compounds of theinvention. For example, the oxazine produced in Example 3 is hereinaftercompared, in its properties, with the corresponding dimethylamino endcompound of Example 3. The end compound is produced from thecorresponding oxazine by prolonged reflux in the presence of aqueousformic acid.

An alternative, and preferred, mode of preparing the compounds of thisinvention involves the reaction of a cycloalkanone or cycloalkenone withan appropriately substituted phenylacetamide anion following theprocedure of Sauvetre et al., ibid., followed by reduction of the amidewith lithium aluminum hydride or a borane reducing agent, except in thecase of cycloaliphatic unsaturation as discussed, supra, to thecorresponding amine. This process is preferred because it isconsiderably more facile when dealing with meta-substituted orhalo-substituted phenylacetamide reactants which pose some problems whenproceeding through the acetonitrile intermediate. This route to thedesired end products also permits one to readily vary the valued R₁ andR₂ in the initial reactant.

The cyano substituent representing R₅ and/or R₆ is introduced after allreduction steps have been completed by displacement of an R₅ -R₆ halosubstitution with cuprous cyanide. The amino substituents representingR₅ and/or R₆ are protected throughout the reaction sequence with aprotecting group such as 1,1,4,4-tetramethyl-1,4-dichlorosilylethylenewhich completely blocks the amino nitrogen atom from undesireablereactions. After completion of the reaction sequence, the amino group isdeprotected and alkylated or acylated by conventional means to provide amono- or di-alkylamine or an alkanamido group in each case of 1 to 6carbo atoms. The nitro substituent representing R₅ and/or R₆ isintroduced as an aromatic substituent by diazotization of the aromaticamine followed by treatment with alkali metal nitrite in the presence ofcopper or by formation of the diazonium tetrafluoroborate and reactionwith an alkali metal nitrite, thusly: ##STR9## The cyano substituent maybe introduced via the diazonium salt with cyprous cyanide in analogousmanner.

The intermediate amide represents an additional aspect of this inventionand is depicted by the following structural formula: ##STR10## in whichthe dotted line represents optional unsaturation,

R₁ is alkyl of 1 to 6 carbon atoms;

R₂ is alkyl of 1 to 6 carbon atoms;

R₄ is hydrogen or alkyl of 1 to 6 carbon atoms;

R₅ and R₆, one of which may be hydrogen, are independently, hydroxyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, aralkoxy of7 to 9 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, alkylmercaptoof 1 to 6 carbon atoms, N-protected amino, halo or trifluoromethyl;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and

n is one of the integers 0, 1, 2, 3 or 4.

When R₄ is alkyl it is introduced prior to reduction. The protectinggroup employed to prevent reaction at the amino substituent representingR₅ and/or R₆ is any protecting group that will completely preventreaction at a primary --NH₂ substituent, such as1,2-[bis-dimethylsilylchloride]ethane.

More indirect routes for synthesis of the antidepressant compounds ofthis invention involve the reaction of a cycloalkanone or acycloalkenone with an anion of an appropriately substituted phenylaceticacid, salt, ester, aldehyde or alcohol ##STR11## where B represents acarboxyl group or its salt or ester or a --CHO or CH₂ OH functionalgroup.

The carboxylic acid group may be converted to an acid halide, activeester or anhydride and directly reacted with the desired amine to yield,after reduction of the resulting amide, the end products of thisinvention. Also, the carboxylic acid group may be reduced withdiisobutyl aluminum hydride or lithium aluminum hydride to obtain thecorresponding aldehyde. The ester is readily converted to the aldehydewith diisobutyl aluminum hydride or to the alcohol with lithium aluminumhydride. The aldehyde may be condensed with hydroxylamine to afford theoxime --CH═NOH; with ammonium or a primary amine to afford an imine--CH═NR₁ or with a primary or secondary amine to afford ##STR12## Thealcohol --CH₂ OH may be converted to the corresponding nitro derivativeby producing an organic sulfonate (mesyl ester) or halide followed bydisplacement with an inorganic nitrite. Reduction of these intermediatesyields the primary amine intermediates or the secondary or tertiaryamine end products of this invention. The alcohols may be converted tomesylates or tosylates, reacted with KCN to afford the nitrile,converted to the amide and subjected to a Hoffman rearrangement withbromine or chlorine and an alkali metal hydroxide.

Additional routes to the desired products include the reaction ofammonia or HNR₁ R₂ with ##STR13## where Z is a leaving group such as ahalogen or an organo sulfonyloxy (mesyl, tosyl and the like) group underconventional conditions. If desired, the amine reactant may be initiallyblocked with a relatively labile acyl group such as trifluoroacetyl toprovide a reactant of the formula ##STR14## prior to reaction with thealkylating reactant employing KOH and a very polar solvent such asdimethylsulfoxide, to provide a tertiary amide from which the acyl groupmay be readily removed to prepare the compound for non-symmetricalN-alkylation to insert R₂. Rather than N-alkylate, one may acylate orreact the secondary amine with an aldehyde and subsequently reduce theamide or Schiff base. Similarly, reaction of the amine with analkylchloroformate affords, upon reduction, an N-methylated amine.LiAlH₄ is a good reducing agent for these processes.

Reductive amination of the aldehyde ##STR15## with ammonia, a primaryamine or a secondary amine (Leuckart reaction) also yields the desiredend products.

During the course of the synthesis of the end compounds of the inventionby means of processes identified above, any hydroxy group represented by--OR₄, R₅ or R₆ may be in the free form or in the form of hydroxyprotected by a removable protecting group, except of course, that thehydroxy group is not protected in any case where it is intended toparticipate in a reaction. The protected form is recommended where thehydroxy group may otherwise undergo an undesired reaction. Examples ofprotecting groups for hydroxy are given in Protective Groups in OrganicChemistry edited by J. F. W. McOmie, Chapters 3 and 4 (pages 95-182),published by Plenum Press (1973), and Protective Groups in OrganicChemistry by T. W. Greene, Chapters 2 and 3 (pages 10 to 113) publishedby John Wiley and Sons (1981). The protecting group may be removed at asuitable later stage in the synthesis. Similarly any amino or alkylaminogroup may be in a protected form where appropriate during the course ofthe synthesis of the end compounds. Protecting groups for amino aredescribed in Chapter 2 (pages 43 to 94) of the McOmie book and Chapter 7(pages 218 to 286) of the Greene book.

The end products contain either one or two asymmetric centers dependingupon the saturated and unsaturated state of the cycloaliphatic ring,respectively. Individual stereoisomeric forms may be obtained orseparated by standard procedures. For instance separation of the mixturein the case of an amine or carboxylic acid may be carried out byneutralisation with a suitable optically active compound to form saltswhich can be separated. Example 33 illustrates the typical resolution ofthe product of Example 3, Compound A.

The antidepressant activity of the end compounds of this invention wasestablished by demonstrating that they (1) inhibit ³ H-imipraminebinding in brain tissue when tested by a method analogous to that ofRaisman et. al., Eur. J. Pharmacol. 61, 373-380 (1980); (2) inhibitsynaptosomal uptake of norepinephrine (³ H--NE) and serotonin (¹⁴C-5-HT) following the test procedure of Wood et. al., J. Neurochem. 37,795-797 (1981); and antagonize reserpine induced hypothermia when testedin accordance with the procedure of Askew, Life Sci. 1, 725-730 (1963).

The results of these procedures affirmed the antidepressant activity ofthe end compounds of this invention in aggreement with the most widelyaccepted theory of antidepressant activity and in correlation ofactivity with known tricyclic antidepressants. In at least twoinstances, namely, with the dimethylamino product of Example 3, and4-chloro product in Example 11, the undesirable attribute of classicalantidepressants observed as an anticholinergic property which isreflected by the inhibition of binding of the muscarinic receptorligand, 3H-quinuclidinyl benzilate (QNB), and in the inhibition ofcarbachol-stimulated contraction of the guinea-pig ileum, is missing.Also missing is the attribute of classical antidepressants observed asan antihistaminic property which is reflected by the inhibition of theH₁ histamine receptor ligand, 3H-pyrilamine, and in the inhibition ofhistamine-stimulated contraction of the guinea-pig ileum.

As representative examples of the activity profile of the end compoundsof this invention, the following data for testing of the dimethylaminoproduct of Example 3, hereinafter Compound A, its oxazine variant,hereinafter Compound B, the 4-chloro product of Example 11, hereinafterreferred to as Compound C, the 4-bromo product of Example 15,hereinafter referred to as Compound D, the 3-chloro product of Example17, hereinafter referred to as Compound E, the 3-bromo product ofExample 16, hereinafter referred to as Compound F, and the 3,4-dichloroproduct of Example 19, hereinafter referred to as Compound G, arepresented as follows:

Inhibition of ³ H-imipramine binding:

Compound A (HCl Salt) exhibited an inhibition constant (K_(i)) vs. ³H-imipramine of 90 nM, making it a fairly potent ligand at this receptorsite. Compound B was somewhat less potent, with a K_(i) of 350 nM.Compound C was virtually equipotent with Compound A, exhibiting a K_(i)vs. ³ H-imipramine of 100 nM. While not as potent as imipramine (K_(i)=1.7 nM), these values fall in the range of desmethylimipramine (DMI)(K_(i) =130 nM) and other tricyclic antidepressants. Atypicalantidepressants (non-tricyclic) which have been tested, exhibit K_(i) 'sgreater than 5000 nM in this assay. Compounds D, E, F and G exhibitedinhibition constants of 62, 130, 52 and 37, respectively. Compounds Athrough G, representative of the other compounds of this invention, arethus comparable to known tricyclic antidepressants in this test.

Inhibition of synaptosomal NE and 5-HT uptake:

Results of the inhibition of NE and 5-HT synaptosomal uptake, expressedas the inhibitory concentration at which the rate of uptake was reducedto 50 percent (IC₅₀), are presented in the table below, where they arecompared with the values for imipramine, DMI and amitriptyline:

    ______________________________________                                        IC.sub.50 (μM)                                                             Compound          NE     5-HT                                                 ______________________________________                                        Imipramine        0.26   0.12                                                 DMI               0.15   3.0                                                  Amitriptyline     0.50   0.60                                                 Compound A        0.64   0.21                                                 Compound B        4.7    2.9                                                  Compound C        0.33   0.25                                                 Compound D        0.21   0.11                                                 Compound E        0.16   0.32                                                 Compound F        0.11   0.23                                                 Compound G        0.07   0.08                                                 ______________________________________                                    

These results show that Compounds A and C to G are approximatelyequipotent to imipramine in NE and 5-HT uptake inhibition. Again,Compound B is somewhat less potent.

Inhibition of ³ H-QNB binding:

In the QNB receptor binding assay, the Compounds A and C-G exhibited anIC₅₀ greater than 10⁻⁵ molar and were therefore essentially inactive.Imipramine and DMI exhibit K_(i) 's of 37 nM and 50 nM, respectively.These results suggest that, unlike the tricyclic antidepressants,Compounds A and C-G would have no muscarinic anticholinergic actions.

Inhibition of Carbachol-stimulated contraction of guinea-pig ileum:

While imipramine at 1 μM exhibits a K_(B) of approximately 100 nMagainst carbachol-stimulated contraction of the guinea-pig ileum,Compound A was inactive at 1 μM. This result supports the suggestion ofa lack of muscarinic anticholinergic action of Compound A.

Inhibition of ³ H-pyrilamine binding:

While DMI exhibits a K_(i) versus ³ H-pyrilamine binding of 124 nM,Compound A was inactive. Compounds D-G exhibited an IC₅₀ greater than10⁻⁵ molar. These results suggest that, unlike tricyclicantidepressants, Compounds A and D-G have no antihistaminic property.

Inhibition of histamine-stimulated contraction of the guinea-pig ileum:

Imipramine at 1 μM inhibits the histamine-stimulated contraction of theguinea-pig ileum with an approximate K_(B) of 8 nM. Compound A, incontrast, had no effect in this test at a concentration of 1 μM. Thisresult supports the notion that Compound A has no antihistaminic action.

Antagonism of reserpine-induced hypothermia:

The minimum effective dose (M.E.D.) of compounds A through G establishedin antagonism of reserpine-induced hypothermia in mice (n=8 per group)in relation to desmethylimipramine (DMI) were:

    ______________________________________                                        Compound     Dose, mg/kg, i.p.                                                ______________________________________                                        DMI          0.4          (and p.o.)                                          A            10.0                                                             B            30.0                                                             C            10.0                                                             D            3.0                                                              E            1.0                                                              F            1.0                                                              G            3.0                                                              ______________________________________                                         All mice received 5 mg/kg reserpine s.c. 18 h prior to test compound.    

DMI, and Compounds A to G, are of approximately equal efficacy in thereversal of reserpine-induced hypothermia. Compound B was less potentthan Compound A, Compound C was approximately equipotent with CompoundA, Compounds D and G were approximately three times as potent asCompound A, and Compounds E and F were approximately ten times as potentas Compound A in the study.

Hence, the end compounds of this invention are useful in the treatmentof depression, for which purpose they may be administered orally orparenterally in an amount sufficient to alleviate the symptoms ofdepression. The actual amount of antidepressant agent to be used willvary with the severity and nature of the depressed state, the animalbeing treated and the level of relief sought. In the human, an oral doseof from about 2 to about 50 milligrams, administered as neededrepresents appropriate posology. Intramuscular administration of fromabout 1 to about 25 milligrams provides a dosage comparable to thatspecified for oral administration. As with other antidepressants,therapy should be initiated with lower dosages and increased until thedesired symptomatic relief is obtained.

Pharmaceutical compositions containing the antidepressant compounds ofthis invention represent an additional aspect of this invention. Theactive ingredient can be compounded into any of the usual oral dosageforms including tablets, capsules and liquid preparations such aselixirs and suspensions containing various colouring, flavouring,stabilizing and flavour masking substances. For compounding oral dosageforms, the active ingredient can be mixed with various conventionaltabletting materials such as starch, calcium carbonate, lactose, sucroseand dicalcium phosphate to aid the tabletting or capsulating process.Magnesium stearate, as an additive, provides a useful lubricant functionwhen desired.

The active ingredients can be dissolved or suspended in apharmaceutically acceptable sterile liquid carrier, such as sterilewater, sterile organic solvent or a mixture of both. Preferably a liquidcarrier is one suitable for parenteral injection. Where the activeingredient is sufficiently soluble it can be dissolved in normal salineas a carrier; if it is too insoluble for this it can often be dissolvedin a suitable organic solvent, for instance aqueous propylene glycol orpolyethylene glycol solutions. Aqueous propylene glycol containing from10 to 75% of the glycol by weight is generally suitable. In otherinstances other compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilised by intramuscular,intraperitoneal or subcutaneous injection.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit doses containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders or vials or ampoules. The unit dosage form can be acapsule, cachet or tablet itself, or it can be the appropriate number ofany of these in package form. The quantity of the active ingredient in aunit dose of composition may be varied or adjusted from 2 mg. or less to50 mg. or more, according to the particular need and the activity of theactive ingredient.

The following examples illustrate the preparative technique employed inproduction of the compounds of the invention.

EXAMPLE 1 1-[Cyano(p-methoxyphenyl)methyl]cyclohexanol

p-Methoxyphenylacetonitrile (50 gm, 0.3 mole) was added to drytetrahydrofuran (250 ml) and the solution cooled to -70° C. undernitrogen. n-Butyl lithium in hexane (210 ml, 0.3 mole) was addeddropwise, with stirring. The temperature was maintained below -50° C.and a yellow precipitate appeared. After the addition was complete, thereaction mixture was maintained below -50° C. for 30 minutes andcyclohexanone (35 ml, 0.3 mole) was added. After a further 45 minutesbelow -50° C. the temperature was allowed to rise to 0° C. and asaturated ammonium chloride solution was added. The layers wereseparated and the aqueous layer extracted with diethyl ether. Thecombined organic solution was washed with brine, dried over magnesiumsulphate and evaporated. The product crystallized (25.2 gm, m.p.125°-127° C.).

Mass Spectral Analysis: Molecular weight 245 [(M+1)⁺ by C.I.M.S.]

N.M.R. Analysis: δ 7.32, 6.95; (4H quartet, p-substituted aromatic) 3.8(3H singlet, O--CH₃); 3.76 (1H, singlet, CH--CN); 1.56 (10H, multiplet,aliphatic cyclohexyl)ppm.

EXAMPLE 2 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol

1-[cyano(p-methoxyphenyl)methyl]cyclohexanol (12 g, 0.05 mole) wasdissolved on warming in a mixture of ammonia-ethanol (20% v/v, 250 ml)and hydrogenated in a Parr apparatus over 5% rhodium on alumina (2.8gm). The catalyst was filtered, washed well with ethanol and thecombined filtrate evaporated and dried under vacuum yielding an oil (12gm).

Mass Spectral Analysis: Molecular weight 249 (M+1)⁺ by C.I.M.S.

Thin Layer Chromatography: single spot, ninhydrin positive[chloroform-methanol-acetic acid (80:10:10 v/v)].

EXAMPLE 3 5-(4-methoxyphenyl)-3-methyl-3-aza-1-oxaspiro(5.5)-undecaneand 1-[2-dimethyl-amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol (12 gm; 0.048 mole) wastreated with a mixture of formaldehyde (11 ml), formic acid (14.5 ml,88%) and water (125 ml) and heated at 100° C. for five hours. Thereaction mixture was cooled and extracted with ethyl acetate. Thisextract was discarded. The aqueous residue was cooled in ice, renderedbasic by the addition of solid potassium hydroxide, saturated withsodium chloride and thrice extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous potassium carbonate andevaporated to an oily residue (8 gm). This mixture of products waschromatographed on 1 kg of Mallinckrodt Silicar CC7 silica gel and theprogress of the chromatography was monitored by thin layerchromatography using a system comprising ethanol:2N ammonia:ethylacetate:cyclohexane 45:8:100:100 (v/v). Fractions containing the desiredproducts were combined and the hydrochloride salts prepared using4-N-isopropanolic HCl. The yields of the free bases were 1.4 gm (spirocompound) and 4.6 gm (dimethylamine) respectively.

COMPOUND B 5-(4-methoxyphenyl)-3-methyl-3-aza-1-oxaspiro(5.5) undecane

Melting Point: 242°-244° C.

Mass Spectral Analysis: Molecular weight 275 (M+1)⁺ by C.I.M.S.

N.M.R. Analysis: δ 7.22, 6.96 (4H quartet, p-substituted aromatic) 4.78(2H quartet, O--CH₂ --NCH₃) 3.8 (4H, O--CH₃, CH--CH₂ --NCH₃) 3.3 (2H,multiplet CH--CH₂ --NCH₃) 2.8 (3H, NCH₃) 0.9-1.8 (10H, broad multiplet,aliphatic cyclohexyl)ppm.

COMPOUND A 1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

The hydrochloride: m.p. 215°-217° C.

Mass Spectral Analysis: Molecular weight 279 (M+1)⁺ by C.I.M.S. (freebase)

N.M.R. Analysis: δ 7.32, 6.98 (4H quartet, p-substituted aromatic) 3.78(3H, O--CH₃) 3.64 (2H, multiplet CH₂ N(CH₃)₂) 3.06 (1H, multipletCH--CH₂ (NCH₃)₂) 2.74 (6H, N(CH₃)₂) 1.38 (10H, broad multiplet, alphaticcyclohexyl)ppm.

EXAMPLE 4 1-[1-(4-methoxyphenyl)-2-dimethylaminoethyl]cyclohexene

8.0 grams (0.029 moles) of1-[1-(4-methoxyphenyl)-2-dimethylaminoethyl]cyclohexanol was dissolvedin 300 ml of 2.0N aqueous hydrochloric acid and heated at reflux for 18hours. It was allowed to cool, neutralized with 15% aqueous sodiumhydroxide and extracted with chloroform. The chloroform extract wasdried over sodium sulfate, filtered, and concentrated in vacuo to yield7.0 grams of solid. This material was converted to the hydrochloridesalt by treatment with 5N isopropanolic HCl and recrystallized a secondtime from isopropanol to yield 2.0 grams of the title compound as awhite solid hydrochloride salt, m.p. 187°-189° C.

Analysis for: C₁₇ H₂₆ ONCl; Calculated: C, 69.23; H, 8.91; N, 4.75;Found: C, 69.39; H, 8.95; N, 4.95.

EXAMPLE 5 1-[(α-Aminomethyl)benzyl]-cyclohexanol

Phenylacetonitrile (10 g, 0.08 mole) was added to dry THF (100 ml) andthe solution cooled to -70° C. under nitrogen. n-Butyllithium in hexane(64 ml, 0.1 mole) was added dropwise, the temperature being maintainedbelow -40° C. and a yellow precipitate appeared. After addition thereaction mixture was maintained near -70° C. for 30 minutes andcyclohexanone (10 g, 0.1 mole) was added. After a further 45 minutes at-70° C. the temperature was allowed to rise to 0° C. and saturatedammonium chloride solution was added. The layers were separated and theaqueous layer extracted with diethyl ether. The combined organicsolution was washed with brine, dried over magnesium sulphate andevaporated. The product, 1-[α-cyanobenzyl]-cyclohexanol, crystallized(4.93 g, m.p. 100°-102° C.).

Mass Spectral Analysis: Molecular weight 215 (M⁺).

N.M.R. Analysis: δ 7.4 (5H singlet, aromatic 3.8 (1H, singlet, CH--CN)1.6 (10H, multiplet aliphatic cyclohexyl) ppm.

A solution of 1-(α-cyanobenzyl)cyclohexanol (3.43 g, 0.02 mole) in amixture of methanol and ammonia (9:1 v/v, 60 ml) was hydrogenated in aParr apparatus over 5% rhodium on alumina (2 g). The catalyst wasfiltered and the filtrate evaporated. The residue was dissolved in ethylacetate, washed with brine, dried over magnesium sulfate and evaporated.The hydrochloride m.p. 220°-222° (1.2 g) crystallized from diethylether-acetone.

Analysis for: C₁₄ H₂₁ NO.HCl; Calculated: C, 64.29; H, 8.67; N, 5.47%;Found: C, 65.74; H, 8.51; N, 5.56%.

N.M.R. Analysis (DMSO) δ 7.73 (5H singlet, aromatic) 3.46 (2H multipletCH₂ --NH₂), 3.0 (1H multiplet CH--CH₂ NH₂) 0.9-1.7 (10Hmultiplet-aliphatic cyclohexyl) ppm.

Mass Spectral Analysis by Chemical Ionization: 220 (M+H)⁺ (Mol. Wt. 219)(free base).

EXAMPLE 6 1-(α-[(Dimethylamino)methyl]benzyl)-cyclohexanol

1-[α-(aminomethyl)benzyl]cyclohexanol (1.38 g, 0.006 mole) was dissolvedin a mixture of formaldehyde (2 ml) formic acid (2.6 ml) and water (25ml), and refluxed at 95° C. for 18 hours. The reaction mixture wascooled, basified with solid KOH and extracted with methylene chloride.The extract was washed with brine, dried over magnesium sulphate andevaporated. The hydrochloride (m.p. 225°-227° C.) was prepared using3N-isopropanolic HCl. Yield 589 mg.

Analysis for: C₁₆ H₂₅ NO.HCl; Calculated: C, 67.36; H, 9.12; N, 4.88%;Found: C, 67.7; H, 9.23; N, 4.93%.

Mass Spectral Analysis: Molecular weight 247 (M⁺, free base).

N.M.R. analysis: (DMSO) δ 7.4 (5H singlet, aromatic), 3.68 (2H,multiplet CH₂ --N (CH₃)₂, 3.18 (1H, multiplet CH--CH₂ N(CH₃)₂ 2.68 (6H,N(CH₃)₂ ; 0.9-1.7 (10H multiplet aliphatic cyclohexyl) ppm.

EXAMPLE 7 1-(α-[(Methylamino)methyl]benzyl)cyclohexanol

1-[α-(aminomethyl)benzyl]cyclohexanol (1.59 g., 0.007 mole) wasdissolved in diethyl ether (10 ml.) and cooled to 5° C. Trifluoroaceticanhydride (2 g) was added and the mixture stirred at 0° C. for 30minutes. The mixture was neutralized using saturated sodium bicarbonatesolution and the layers separated. The organic layer was washed withbrine, dried over magnesium sulphate and evaporated. A crystallinetrifluoroacetamide m.p. 78°-80° C. was obtained (975 mg.).

The trifluoroacetamide (975 mg.) was dissolved in dry acetone (20 ml.)and treated with methyl iodide (2 g.). The solution was warmed to refluxtemperature and dry powdered potassium hydroxide (1 g.) added, followedby excess methyl iodide. The mixture was refluxed for five minutes, thencooled and the acetone evaporated. Water (20 ml.) was added and themixture refluxed for 15 minutes. It was cooled and extracted with ethylacetate. The extract was washed with water and brine, dried overmagnesium sulfate and evaporated to a crystalline product m.p. 92°-94°C. This was converted to the hydrochloride using 3N-isopropanolic HCl.Yield 235 mg., m.p. 208°-210° C.

N.M.R. Analysis (CHCl₃), δ 7.3 (7H, aromatic, HCl and NH.CH₃); 3.9 (1Hmultiplet CH--CH₂ NH₂); 3.25 (2H multiplet CH₂ --NH₂); 2.6 (3H singletNH--CH₃); 0.8-1.9 (10H multiplet, aliphatic cyclohexyl) ppm.

Mass Spectral Analysis: Molecular weight by chemical ionization/M.S. 233(M+1 at 234, free base).

EXAMPLE 8 1-(α-[(Dimethylamino)methyl]benzyl)cyclohexanol acetate

1-(α-[(Dimethylamino)methyl]benzyl)cyclohexanol, (0.5 g., 0.0025 mole)was treated with acetic anhydride (1 ml.) and pyridine (3 ml.) and themixture stood at room temperature overnight. The reaction mixture waspoured into water, basified with solid KOH and extracted with ethylacetate. The extract was washed with water and brine, dried overmagnesium sulphate and evaporated to an oil. After azetropicdistillation with toluene to remove traces of pyridine, the oil wastreated with 3N isopropanolic HCl and crystalline hydrochloride as thetitle compound was obtained (70 mg.) m.p. 163°-165° C.

NMR Analysis: (CHCl₃) δ 7.35 (5H singlet, aromatic); 4.2 (1H multipletCHCH₂ N(CH₃)2; 3.6 (2H multiplet CH₂ --N(CH₃)₂); 2.65 (6H singlet,N(CH₃)₂); 2.1 (3H singlet, --O--C--CH₃); 0.9-1.7 (10H multiplet,aliphatic cyclohexyl) ppm.

Mass Spectral Analysis: Molecular weight 289 (M⁺, free base).

EXAMPLE 9 1-[cyano(p-chlorophenyl)methyl]cyclohexanol

By replacing the p-methoxyphenyl acetonitrile in Example 1 by a molarequivalent amount of p-chlorophenyl acetonitrile, there was obtained1-cyano(p-chlorophenyl)methyl cyclohexanol (13.7 g.) m.p. 115°-117°.

Mass Spectral Analysis: Molecular weight 249 (M+1)⁺ by C.I.M.S.

EXAMPLE 10 1-[2-amino-1-(4-chlorophenyl)ethyl]cyclohexanol

Lithium aluminum hydride (3.5 g.) was suspended in ice coldtetrahydrofuran (125 ml.) and concentrated sulphuric acid (2.5 ml.)added cautiously, with stirring. After one hour,1-[cyano(p-chlorophenyl)methyl]cyclohexanol (15 g., 0.06 mole) wasdissolved in tetrahydrofuran (100 ml.) and added rapidly dropwise withvigorous stirring and cooling. After a further two hours, atetrahydrofuran-water mixture (1:1; 30 ml.) was added followed by 10%sodium hydroxide solution (50 ml.). The tetrahydrofuran was decanted andthe residue washed well with diethyl ether and ethylacetate. Thecombined organic solution was dried over anhydrous potassium carbonateand evaporated to an oil (12 g.)

Mass Spectral Analysis: Molecular weight 253 (M+1)⁺ by C.I.M.S.

EXAMPLE 11 1-[1-(4-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol

1-[2-amino-1-(4-chlorophenyl)ethyl]cyclohexanol (12 g., 0.04 mole) wastreated with a mixture of formaldehyde (13.7 ml.) formic acid (18.1 ml.)and water (160 ml.) and refluxed at 100° C. for four hours. The reactionmixture was cooled extracted well with ethyl acetate and the extractdiscarded. The aqueous residue was cooled in ice and rendered basic bythe addition of solid potassium hydroxide, saturated with sodiumchloride and thrice extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous potassium carbonate and evaporated. Acrystalline solid (3 g.) was filtered. It was converted to thehydrochloride salt using 4N-isopropanolic HCl; yielding 4.7 g., m.p.241°-243° C.

Mass Spectral Analysis: Molecular Weight 281 (M+1)⁺ by C.I.M.S.

NMR Analysis: δ 7.35 (4H singlet characteristic of 4-chlorosubstitution) 3.65 (2H multiplet, CH₂ --CHN(CH₃)₂), 3.0 (1H multipletCH₂ CHN(CH₃)₂ 1.4 (10H multiplet, aliphatic cyclohexyl) ppm.

EXAMPLE 12 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol

By replacing 1-[α-(aminomethyl)benzyl]cyclohexanol with a molarequivalent amount of 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol inExample 7, 1-[1-(4-methoxyphenyl)-2-methylamino)ethyl]cyclohexanolhydrochloride (m.p. 164°-166° C.) was obtained.

Mass Spectral Analysis: Molecular Weight 263 (M+1)⁺ by C.I.M.S.

NMR Analysis: δ 7.28, 6.92 (4H quartet, p-substituted aromatic) 3.76 (3Hsinglet, OMe) 3.4 (2H multiplet, CH₂ --CHNCH₃)₂ 2.9 (1H multiplet, CH₂CHN(CH₃)₂) 2.54 (3H, NCH₃) 1.4 (10H broad multiplet, aliphaticcyclohexyl) ppm.

EXAMPLE 13 4-bromo-N,N-dimethylbenzene acetamide

Para-bromophenylacetic acid (50 g., 0.233 mole) was dissolved inmethylene chloride (500 ml) and treated with oxalyl chloride (23.3 ml.,0.27 mole) and D.M.F. (0.5 ml) at room temperature. The mixture wasstirred for four hours until gas evolution ceased. The solvent wasevaporated and the residue dried under vacuum to remove excess oxalylchloride. The residue was dissolved in methylene chloride (300 ml) andtreated with an excess of gaseous dimethylamine. The mixture was stirredovernight and the solvent evaporated. The residue was redissolved inmethylene chloride and the solution washed with saturated sodiumbicarbonate solution, N-hydrochloric acid, water, brine, dried overmagnesium sulphate and evaporated. The buff-colored crystals werefiltered with hexane and air-dried. Yield 51.2 g., m.p. 73°-76° C.

Analysis for: C₁₀ H₁₂ NOBr; Calculated: C, 49.59; H, 4.96; N, 5.79;Found: C, 48.98; H, 5.14; N, 5.77.

NMR Analysis (CHCl₃): δ 7.55 (4H quartet, aromatic) 3.65 (2H singlet)2.95 (6H singlet, N(CH₃)₂) ppm.

EXAMPLE 141-[(4-bromophenyl)[(dimethylamino)carbonyl]methyl]cyclohexanol

4-bromo-N,N-dimethylbenzene acetamide (15 g., 0.06 mole) was added todry T.H.F. (250 ml) and the solution cooled to -78° C. under nitrogen.Straight chain butyl lithium in hexane (43.3 ml, 0.06 mole) was addeddropwise, the temperature being maintained below -70° C. throughout. Anorange coloured precipitate formed. After addition, the reaction mixturewas maintained near -70° C. for 20 minutes and cyclohexanone (7.5 ml,0.07 mole) was added. After a further 50 minutes at -78° C. the reactionmixture was poured into stirring saturated ammonium chloride solution.The layers were separated and the aqueous layer extracted with diethylether. The combined organic solution was washed with brine, dried overmagnesium sulfate and evaporated. The product crystallised and wasfiltered with isopropanol (9.8 g., m.p. 140°-144° C.).

Analysis for: C₁₆ H₂₂ NO₂ Br; Calculated: C, 56.47; H, 6.47; N, 4.12;Found: C, 57.22; H, 6.66; N, 4.21.

NMR Analysis (CHCl₃) δ 7.35 (4H, aromatic) 3.63 (1H singletCH--CON(CH₃)₂) 2.95 (6H singlet, N--(CH₃)₂); 1.45 (10H multiplet,aliphatic cyclohexyl) ppm.

EXAMPLE 15 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol

Lithium aluminum hydride (0.7 g.) was suspended in dry THF (25 ml)cooled to 0° C. and concentrated sulfuric acid (0.5 ml) cautiously addedin an in situ preparation of aluminum hydride. The mixture was stirredfor one hour at 0° C. and the amide,1-[(4-bromophenyl)[dimethylaminocarbonyl]methyl]cyclohexanol (4 g.,0.012 mole) was dissolved in THF (35 ml) and added rapidly dropwise. Thereaction mixture was stirred at 0° C. for one hour. A THF-water mixture(1:1 v/v 6 ml) was added slowly followed by 10% sodium hydroxide (10ml). The mixture was filtered and the residue washed well with ethylacetate. The combined filtrate was dried over anhydrous potassiumcarbonate and evaporated to an oil (3.5 g) which was converted to thehydrochloride salt using 4N isopropanolic HCl.

Analysis for: C₁₆ H₂₄ NOBr.HCl; Calculated: C, 52.97; H, 6,9; N, 3.86;Found: C, 52.71; H, 6.63; N, 3.71.

NMR Analysis: (DMSO): δ 7.4 (4H, aromatic) 3.55 (2H doublet CH--CH₂N(CH₃)₂); 3.05 (1H, triplet, CH--CH₂ N(CH₃)₂); 2.63 (6H singlet,N--(CH₃)₂) 1.30 (10H multiplet, aliphatic cyclohexyl) ppm.

EXAMPLE 16 1-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofm-bromophenyl acetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol was obtained asthe hydrochloride, m.p. 198°-201° C.

Analysis for: C₁₆ H₂₄ NOBr.HCl; Calculated: C, 52.97; H, 6.90; N, 3.86;Found: C, 52.84; H, 6.92; N, 3.99.

EXAMPLE 17 1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofm-chlorophenylacetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol was obtainedas the hydrochloride, m.p. 214°-216° C.

Analysis for: C₁₆ H₂₄ NOCl.HCl; Calculated: C, 60.38; H, 7.86; N, 4.4;Found: C, 60.07; H, 7.79; N, 3.93.

EXAMPLE 18 1-[1-(2-Chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofo-chlorophenylacetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[1-(2-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol was obtainedas the hydrochloride, m.p. 205°-206° C.

Analysis for: C₁₆ H₂₄ NOCl.HCl; Calculated: C, 60.38; H, 7.86; N, 4.4;Found: C, 60.45; H, 7.71; N, 4.79.

EXAMPLE 19 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount of3,4-dichlorophenylacetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[1-(3,4-dichlorophenyl-2-(dimethylamino)ethyl]cyclohexanol wasobtained as the hydrochloride, m.p. 241°-244° C.

Analysis for: C₁₆ H₂₃ NOCl₂.HCl; Calculated: C, 54.47; H, 6.81; N, 3.97;Found: C, 54.8; H, 6.83; N, 3.99.

EXAMPLE 20 1-[1-(3,4-dichlorophenyl-2-(dimethylamino)ethyl]cyclohexanol

The product of the preceding example is similarly produced by thefollowing procedure:

Lithium diisopropylamide was prepared by dissolving di-isopropylamine(69 ml) in THF (500 ml) followed by the addition of n-butyllithium (325ml). After 10 minutes stirring, the straw colored liquid was cooled to-78° C. and a solution of the 3,4-dichloro-N,N-dimethylbenzeneacetamide(110.9 g, crude) was dissolved in 300 ml THF and added slowly. A darkred slurry was obtained. The mixture was stirred for a further 20minutes and cyclohexanone (55.7 ml) was added. After 60 minutes at -78°C. the reaction mixture was poured into a saturated solution of ammoniumchloride. The aqueous layer was extracted with diethyl ether and thecombined organic solution was washed with brine, dried over K₂ CO₃ andevaporated. The product,1-[(3,4-dichlorophenyl)(dimethylaminocarbonyl)methyl]cyclohexanol,crystallized and was filtered. The crystals were washed with isopropanoland with petroleum ether and air dried. Yield: 73.6 g., m.p. 118°-120°C.

To an ice cold solution of Borane THF complex (152 ml, 152 mmole) wasadded a solution of1-[(3,4-dichlorophenyl)(dimethylaminocarbonyl)methyl]cyclohexanol (30 g,90 mmole) in THF. The mixture was refluxed for 2 hours and cooled againin an ice bath. 2N HCl (23 ml) was added and the mixture refluxed for1.5 hours. It was cooled overnight. The reaction mixture was basified topH 14 with solid potassium hydroxide and the layers were separated. Theorganic layer was washed with brine, dried over magnesium sulfate andevaporated to a solid. This was filtered and washed with diethyl etherand air dried. Yield: 15.4 g.; m.p. 128°-130° C.

This product was converted to the hydrochloride which was identical withthe product in Example 19.

EXAMPLE 21 1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofm-methoxyphenyl acetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohexanol was obtainedas the hydrochloride, m.p. 166°-168° C.

Analysis for: C₁₆ H₂₅ NO₂.HCl; Calculated: C, 64.11; H, 8.68; N, 4.67;Found: C, 63.12; H, 8.54; N, 4.46.

EXAMPLE 221-[1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount of3,4-dimethoxyphenyl acetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[1-(3,4-dimethoxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol wasobtained as the hydrochloride.

Analysis for: C₁₈ H₂₉ NO₃.HCl; Calculated: C, 62.88; H, 8.74; N, 4.08;Found: C, 62.42; H, 8.56; N, 3.98.

EXAMPLE 231-[2-(dimethylamino)-1-(4-trifluoromethylphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofp-trifluoromethylphenyl acetic acid in Example 13, and followingprocedures described in Examples 14 and 15,1-[2-(dimethylamino)-1-(4-trifluoromethylphenyl)ethyl]cyclohexanol wasobtained as the hydrochloride, m.p. 238°-240° C.

Analysis for: C₁₇ H₂₅ NOF₃.HCl; Calculated: C, 58.03; H, 7.16; N, 3.98;Found: C, 58.47; H, 7.16; N, 4.07.

EXAMPLE 241-[2-(dimethylamino)-1-(3-trifluoromethylphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofm-trifluoromethylphenyl acetic acid in Example 13, and followingprocedures described in Examples 14 and 15,1-[2-(dimethylamino)-1-(3-trifluoromethylphenyl)ethyl]cyclohexanol wasproduced as the hydrochloride, m.p. 194°-196° C.

Analysis for: C₁₇ H₂₅ NOF₃.HCl; Calculated: C, 58.03; H, 7.16; N, 3.98;Found: C, 58.31; H, 7.09; N, 4.09.

EXAMPLE 25 1-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofp-methylphenyl acetic acid in Example 13, and following proceduresdescribed in Examples 14 and 15,1-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexanol was producedas the hydrochloride.

Analysis for: C₁₇ H₁₇ NO.HCl; Calculated: C, 68.54; H, 9.17; N, 4.70;Found: C, 68.37; H, 9.31; N, 4.83.

EXAMPLE 26 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofp-benzyloxyphenyl acetic acid in Example 13, and following theprocedures described in Examples 14 and 15,1-[1-(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol wasobtained.

Hydrogenolysis of this product to remove the benzyl protecting groupfrom the 4-hydroxyphenyl moiety was accomplished by dissolving 1.0 gramsof the product in 100 ml. ethanol. One gram, 10% Pd/C was introducedfollowed by cyclohexa-1,4-dienone (5 ml.). The mixture was stirred forninety minutes at ambient temperature. The catalyst was removed byfiltration and the solvent removed by evaporation to yield 800 mg. ofsolid. This solid 4-hydroxyphenyl product was converted to its fumaratesalt via an acetone-ethanol solution, m.p. 140°-142° C.

Analysis for: C₁₆ H₂₅ NO₂.C₄ H₄ O₄ ; Calculated: C, 63.30; H, 7.70; N,3.69; Found: C, 62.18; H, 7.90; N, 3.63.

EXAMPLE 27 1-[2-(dimethylamino)-1-(3-hydroxyphenyl)ethyl]cyclohexanol

By replacing p-bromophenyl acetic acid with a molar equivalent amount ofm-benzyloxyphenyl acetic acid in Example 13, and following theprocedures described in Example 14 and 15,1-[1-(3-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol wasobtained.

Hydrogenolysis of this product (2.3 g) was conducted in 200 ml ethanolemploying a Paar bomb, 300 mg. 10% Pd/C until uptake of hydrogen ceased.The catalyst was removed by filtration and the solvent evaporated toafford a solid product which was converted to its hydrochloride saltwith 5N isopropanolic hydrochloride, m.p. 162°-164° C.

Analysis for: C₁₆ H₂₅ NO₂.HCl; Calculated: C, 64.08; H, 8.74; N, 4.67;Found: C, 62.78; H, 8.55; N, 4.55.

EXAMPLE 28 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclobutanol

By replacing cyclohexanone in Example 14 with a molar equivalent amountof cyclobutanone and following the procedure described in Example 15,1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclobutanol was obtained.It was converted to the hydrochloride salt, m.p. 220°-222° C.

Analysis for: C₁₄ H₂₀ NOBr.HCl; Calculated: C, 50.22; H, 6.28; N, 4.19;Found: C, 50.26; H, 6.11; N, 4.13.

EXAMPLE 29 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclopentanol

By replacing p-bromophenylacetic acid with a molar equivalent amount ofp-methoxyphenyl acetic acid in Example 13, 4-methoxy-N,N-dimethylbenzeneacetamide was obtained. Subsequently, following the procedure outlinedin Example 14, replacing cyclohexanone with a molar equivalent amount ofcyclopentanone, there was obtained the corresponding cyclopentanolderivative. This intermediate was converted, following the proceduredescribed in Example 15, to the title compound as the hydrochloride,m.p. 194° C.

Analysis for: C₁₆ H₂₅ NO₂.HCl; Calculated: C, 64.07; H, 8.76; N, 4.67;Found: C, 64.19; H, 8.72; N, 4.33.

EXAMPLE 30 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cycloheptanol

By replacing cyclopentanone with a molar equivalent of cycloheptanone inExample 27, the title compound was obtained as the hydrochloride, m.p.175°-177° C.

Analysis for: C₁₈ H₂₉ NO₂.HCl.1/4H₂ O; Calculated: C, 65.03; H, 9.26; N,4.21; Found: C, 65.25; H, 9.16; N, 4.29.

EXAMPLE 31 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclooctanol

By replacing cyclopentanone with a molar equivalent amount ofcyclooctanone in Example 29, the title compound was obtained as thehydrochloride, m.p. 178°-180° C.

Analysis for: C₁₉ H₃₁ NO₂.HCl.1/4H₂ O; Calculated: C, 65.87; H, 9.48; N,4.04; Found: C, 65.79; H, 9.08; N, 3.95.

EXAMPLE 321-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohex-2-en-1-ol

By replacing 4-bromo-N,N-dimethylbenzeneacetamide with a molarequivalent of 4-methoxy-N,N-dimethylbenzeneacetamide in Example 14, andcyclohexanone with 2-cyclohexen-1-one, was obtained the correspondingcyclohexenone derivative. This intermediate was converted following theprocedure described in Example 15 to the title compound as the fumarate,m.p. 128°-130° C.

Analysis for: C₁₇ H₂₅ NO₂.C₄ H₄ O₄ ; Calculated: C, 64.4; H, 7.31; N,3.58; Found: C, 63.8; H, 7.46; N, 3.88.

EXAMPLE 33 Resolution of Racemic1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol

1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol (48.0 g.,0.173 m) dissolved in ethyl acetate (350 ml) was treated withdi-p-toluoyl-d-tartaric acid (33.5 g., 0.082 m) dissolved in ethylacetate (250 ml). After standing overnight, the solid was filtered. Thesolid was recrystallized three times by dissolving in boiling ethylacetate (300 ml) and methanol (50 ml), concentrating by boiling toincipient crystallization and chilling. Yield 31.7 g., m.p. 126°-128° C.[α]_(D) ²⁵ =-50.51; c=1.03 ethanol.

The salt was converted to its free base by shaking in 2N sodiumhydroxide and diethyl ether. The ether layer was washed with brine,dried over anhydrous sodium carbonate, evaporated and dried in vacuo.Yield 16.4 g., 68.5%. m.p. 104°-5° C. [α]_(D) ²⁵ =+27.95; c=1.15, 95%ethanol.

The base was dissolved in ether (500 ml) and treated with 4.5N hydrogenchloride in isopropanol (20 ml). The resulting hydrochloride salt wasrecrystallized from warm methanol (75 ml) by dilution with ether (400ml) and chilling. Yield 16.6 g. m.p. 239°-241° C. [α]_(D) ²⁵ =-4.38;c=1.01, 95% ethanol.

The filtrate and washings from the original di-p-toluoyl-d-tartrate saltwere evaporated to dryness. The free base was obtained by shaking thesolid with 2N sodium hydroxide (400 ml), extracting with diethyl ether(3×250 ml), washing the extracts with brine and drying. Yield 24.2 g.The base was dissolved in ethyl acetate (150 ml) and treated withdi-p-toluoyl-l-tartaric acid (16.75 g, 0.0435 m) dissolved in ethylacetate (150 ml). After standing overnight the salt was filtered and wasrecrystallized twice from ethyl acetate (300 ml) and methanol (50 ml) asdescribed. Yield 29.4 g. m.p. 124°-127° C. [α]_(D) ²⁵ =+50.77, c=0.845ethanol.

The base was obtained in the manner described. Yield 14.7 g. m.p.104°-105° C. [α]_(D) ²⁵ =-26.56, c=1.22%, 95% ethanol.

The free base was converted to the hydrochloride salt.

Yield 14.5 g. m.p. 239°-241° C. [α]_(D) ²⁵ =+4.98, c=1.01, 95% ethanol.

EXAMPLE 34 1-[1-(4-aminophenyl)-2-dimethylaminoethyl]cyclohexanol

17.0 g (0.095 moles) of p-aminophenylacetic acid, dimethylamide wasdissolved in 500 ml of tetrahydrofuran, placed under a nitrogenatmosphere, and cooled to -20° C. 23.6 g (1.15 equivalents) of1,1,4,4-tetramethyl-1,4-dichlorosilylethylene was added, followeddropwise by a solution of 42 g (2.4 equivalents) of sodiumbis(trimethylsilyl)amide in 250 ml of THF. The mixture was allowed towarm to room temperature and was stirred for 18 hours.

The mixture was next cooled to -78° C. and 71.6 ml (1.2 equivalents) of1.6N n-butyl lithium in hexane added. The reaction was stirred for 45minutes and then 20 ml (2.0 equivalents) of cyclohexanone added. Themixture was stirred for an additional 1 hour at -78° C. and then pouredinto a saturated aqueous solution of ammonium chloride. The organicphase was removed and the aqueous phase was extracted with diethylether. The combined organic phases were dried over sodium sulfate,filtered and concentrated in vacuo to yield 20 g of crude1-[(4-aminophenyl)(dimethylaminocarbonyl)methyl]cyclohexanol. Columnchromatography on silica gel with 1% methanol in methylene chloride gave16 g of essentially pure white solid. A sample twice recrystallized fromethanol had m.p. 169°-170° C. and the following elemental analysis:

Analysis for: C₁₆ H₂₄ O₂ N₂ ; Calculated: C, 69.51; H, 8.77; N, 10.14;Found: C, 69.69; H, 8.96; N, 10.26.

5.0 g (0.018 mole) of the above amide was dissolved in 300 ml of drytetrahydrofuran and added dropwise to a mixture of 1.1 g of lithiumaluminum hydride and 8.0 ml of concentrated sulfuric acid in 200 ml oftetrahydrofuran at 0° C. The mixture was stirred at 0° C. for fivehours, then the excess reagent was destroyed by the dropwise addition of4 ml of 50:50 THF-water, then 4 ml of 15% aqueous sodium hydroxide andfinally 4 ml of water. The mixture was filtered and the precipitatewashed several times with THF. The combined filtrates were evaporatedand the residue recrystallized from isopropanol to give 3.8 g of thetitle compound as the free base. Treatment with excess oxalic acid inethyl acetate gave the dioxalate, m.p. 105° C.(d).

Analysis for: C₂₀ H₃₀ N₂ O₉ ; Calculated: C, 54.28; H, 6.84; N, 6.33;Found: C, 53.96; H, 6.83; N, 6.24.

EXAMPLE 35 1-[1-(4-nitrophenyl)-2-dimethylaminoethyl]cyclohexanol

2.0 g (7.6 mmoles) of1-[1-(4-aminophenyl)-2-dimethylaminoethyl]cyclohexanol was dissolved in50 ml of methylene chloride and added dropwise to a stirring solution of2.2 g (2.5 equivalents) of nitrosonium tetrafluoroborate. The reactionwas stirred at room temperature for four hours. The methylene chloridewas then removed in vacuo and replaced with 100 ml of water. Thissolution was added slowly to a mixture of 2.0 g of copper in 200 ml of1N sodium nitrite and the combination stirred for 2 hours at roomtemperature. Extraction with methylene chloride, drying, and evaporationin vacuo yielded 2.0 g of the free base of the title compound.Recrystallization from isopropanolic HCl gave the hydrochloride, m.p.211°-212° C.

Analysis for: C₁₆ H₂₄ O₃ N₂ ; Calculated: C, 58.42; H, 7.37; N, 8.52;Found: C, 58.03; H, 7.53; N, 8.69.

EXAMPLE 361-[2-dimethylamino)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol

By replacing 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol in Example3 with a molar equivalent amount of1-[2-amino-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol and refluxingovernight, the title compound was obtained, m.p. 218°-220° C.

Analysis for: C₁₇ H₂₆ NO₂ Br.HCl; Calculated: C, 57.98; H, 6.92; N,3.56; Found: C, 51.57; H, 6.79; N, 3.46.

EXAMPLE 37 2-[1-(dimethylamino)-2-(4-methoxyphenyl)propyl]cyclohexanol

14.7 g (0.10 mole) of p-methoxyphenylacetonitrile was dissolved in 250ml of dry tetrahydrofuran and placed in a dry ice/isopropanol bath underN₂. 69.0 ml of 1.6M n-butyl lithium (0.11 mole) was added dropwise over30 minutes and the mixture stirred at -78° C. for one hour. The lithiumsalt of the nitrile precipitated as a yellow solid during this time.71.0 g (0.50 mole) of methyl iodide was then added and stirring at -78°C. continued for an additional hour. The mixture was then poured intosaturated ammonium chloride and the product extracted into diethylether, washed with saturated sodium chloride and dried over sodiumsulfide. It was filtered and evaporated, redissolved in methylenechloride and passed through Florisel®. Evaporation gave 15.0 g ofα-(p-methoxyphenyl)propionitrile as an orange oil.

The α-(p-methoxyphenyl)propionitrile prepared above was redissolved in250 ml of tetrahydrofuran and cooled to -78° C. in dry ice/isopropanol.69.0 ml of 1.6M n-butyllithium was added over 30 minutes and the mixturestirred for 1 hour under nitrogen. 20 ml of cyclohexanone was then addedand stirring at 078° C. was continued for an additional hour. Themixture was poured into saturated ammonium chloride solution and theproduct extracted with diethyl ether. It was washed with water,saturated sodium chloride and dried over sodium sulfate. Filtration andevaporation gave 21.5 g of white solid. A sample twice recrystallizedfrom benzene had m.p. 129° C. and the following analysis:

Analysis for: C₁₆ H₂₁ NO₂ ; Calculated: C, 74.10; H, 8.16; N, 5.40;Found: C, 73.95; H, 8.04; N, 5.29.

4.0 g (15 mmoles) of the β-hydroxynitrile prepared above was dissolvedin 200 ml of tetrahydrofuran and 50 ml of 1M borane tetrahydrofurancomplex was added. The mixture was refluxed for 2 hours and allowed tocool. 200 ml of 2N HCl was added and the THF removed in vacuo. Theaqueous solution was made basic by the addition of solid potassiumcarbonate and the product extracted with 500 ml of ethyl acetate, washedwith saturated sodium chloride and dried over sodium sulfate. This wasfiltered and evaporated and treated with isopropanolic HCl and diethylether to yield 3.3 g of the primary amine, m.p. 209° C.

Analysis for: C₁₆ H₂₆ NO₂ Cl; Calculated: C, 64.09; H, 8.74; N, 4.67;Found: C, 63.70; H, 8.60; N, 4.59.

3.0 g (10 mmole) of the primary amine hydrochloride was dissolved in 200ml of absolute ethanol. 5.0 ml of 37% aqueous formaldehyde and 1.0 g of10% palladium on carbon were added and the mixture was treated with 50psi of hydrogen on a Parr shaker for 3 days. The mixture was thenfiltered and evaporated and the solvent replaced with 300 ml of waterand washed with 300 ml of ethyl acetate. The aqueous solution was thenmade pasic with solid sodium carbonate and again extracted with ethylacetate. The organic extract was washed with saturated brine and driedover sodium sulfate. It was filtered and evaporated and the titlecompound precipitated as the hydrochloride from isopropanol/ether by theaddition of isopropanolic HCl. A second crystallization from isopropanolgave 2.0 g of white solid, m.p. 271° C.

EXAMPLE 38

By following a procedure similar to Examples 13 to 15, using (a)3,4-dibromophenylacetic acid, (b) 3-methylphenylacetic acid, (c)4-bromophenylacetic acid and (d) 3-methoxyphenylacetic acid instead ofp-bromophenylacetic acid and, as the cycloalkanone, (a) cyclohexanone,(b) cyclohexanone, (c) cyclobutanone and (d) cyclopentanone, there areprepared (a)1-[1-(3,4-dibromophenyl)-2-(dimethylamino)ethyl]cyclohexanol, (b)1-[2-(dimethylamino)-1-(3-methylphenyl)ethyl]cyclohexanol, (c)1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclobutanol and (d)1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclopentanol.

What is claimed is:
 1. A compound of the formula: ##STR16## in which thedotted line represents optional unsaturation, and R₄ is hydrogen oralkyl of 1 to 6 carbon atoms;R₅ and R₆, one of which may be hydrogen,are ortho or para substituents, independently selected from the groupconsisting of hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, aralkoxy of 7 to 9 carbon atoms, alkanoyloxy of 2 to 7carbon atoms, alkylmercapto of 1 to 6 carbon atoms, halo ortrifluoromethyl; R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and nis one of the integers 0, 1, 2, 3 or
 4. 2. The compound of claim 1 whichis 1-[cyano(p-methoxyphenyl)methyl]cyclohexanol.
 3. The compound ofclaim 1 which is 1-[cyano(p-chlorophenyl)methyl]cyclohexanol.
 4. Thecompound of claim 1 which is1-[cyano(3-bromo-4-methoxyphenyl)methyl]cyclohexanol.
 5. The compound ofclaim 1 which is 1-[2-cyano-2-(4-methoxyphenyl)ethyl]cyclohexanol.